While considerable progress has been made in the treatment of rheumatoid arthritis (RA), only a minority of patients treated with optimal regimens of disease-modifying anti-rheumatic drugs achieve a clinical remission. Achieving a clinical remission is a desired goal of therapy because it is associated with minimal or no radiographic progression of joint destruction. To this end, we are proposing a randomized, double-blind, placebo-controlled trial in early RA comparing remission rates obtained following treatment with methotrexate (MTX) plus abatacept versus MTX and an anti-tumor necrosis factor (TNF) inhibitor. The proposed study design includes a novel withdrawal phase during which patients achieving a minimal level of disease activity will discontinue their assigned treatment, namely abatacept or a TNF inhibitor, and be followed for an additional 9 months to evaluate for sustained clinical remission. We propose to integrate a number of mechanistic studies into the trial aimed at identifying prognostic biomarkers of treatment response. To achieve the ambitious aims of such a comprehensive research strategy will require an intensive 12-month planning phase, which is the focus of the proposed project. The project will be led by Dr. E. William St.Clair, an experienced clinical investigator with expertise in the treatment of RA. The aims of the planning phase are as follows: 1) To effectively utilize a Steering Committee of disease experts and the assets of the Duke Clinical Research Institute to develop an optimal clinical trial design and guide other important phases of protocol development; 2) To develop a research strategy for identifying biomarkers of treatment response using a variety of uniplex and multiplex assay platforms; and 3) To develop an effective collaboration with the Immune Tolerance Network to obtain access to their multiplex assay platforms, including RNA expression arrays and high throughput flow cytometry, as well as analytical tools to implement the goals of specific aim 2. The support for this planning phase will enable us to produce the key deliverables of clinical protocol development, a highly integrated set of innovative biomarker studies, and a robust infrastructure for trial implementation, with the overall goal of submitting an outstanding application to NIAMS for funding of the proposed clinical trial. Therapies designed to achieve remission and tailored for people's distinct genetic make-up and other factors are the next major steps in the management of rheumatoid arthritis (RA). Research has already shown that such therapies can benefit public health. The proposed clinical trial will compare the remission-inducing capabilities of two novel therapies for early RA, and search for biomarkers that predict treatment response. [unreadable] [unreadable] [unreadable] [unreadable]